Agrin: Agrin is a signaling protein made in motor neurons that is essential for postsynaptic differentiation at the NMJ, which has been a research focus in the Burgess lab for several years. We continue to work on Agrin, examining its roles in maintaining the NMJ postnatally and with age. In addition, Agrin mutations in people cause myasthenias, diseases characterized by a breakdown in the NMJ. Thus, understanding Agrin’s role at the NMJ is very important. In addition, Agrin is an extacellular matrix molecular found in many sites, and may have additional varied roles including contributions to the integrity of the blood brain barrier and central nervous system functions. The genetic resources developed by the Burgess lab will be useful tools for further study of Agrin in many settings.
Charcot-Marie-Tooth peripheral neuropathies: We are also working to understand how dominant mutations in glycyl tRNA synthetase (GARS) cause Charcot-Marie-Tooth type 2D in humans and a very similar disease in mice. The only known function of GARS is the charging of glycine onto its cognate tRNAGly during translation. Our previous studies on Gars mutant mice indicate that the peripheral neuropathy is not related to this known function of the protein, and suggest that the mutant forms of the protein are assuming novel, pathogenic functions. We are working to understand these putative novel functions through a combination of approaches, including an integrated analysis of transcription and translation in peripheral neurons. In addition, these mice serve as an excellent preclinical model for testing therapies, including possible pharmaceutical or gene therapy-based approaches.
In addition to GARS, a variety of other genes associated with human peripheral neuropathy and axon degeneration are also being studied in the Burgess lab, and we are constantly vigilant for new mutations that present with neuromuscular dysfunction. We currently study several human neuropathy models as well as novel mouse mutations that affect the NMJ. These models and mutations are at various stages of characterization.
To expand our research on synapse formation to the central nervous system, we recently identified a mutation that affects the development of the retina. The mutation is in the gene encoding Down syndrome cell adhesion molecule (Dscam). In the absence of Dscam, neurons in the retina fail to arborize their processes, and neurons of the same cell type (dopaminergic amacrine cells for example) fasciculate and clump, destroying their normally even lateral mosaic spacing. We are now examining Dscam’s role in other neuronal populations in the retina and in other parts of the central nervous system. In addition, we have generated mutations in the closely related gene Dscam-Like1 (Dscaml1). This gene has a phenotype similar to, but distinct from, the Dscam mutation. Dscams function in self-recognition and self-avoidance among neuronal populations, and as such, they are adhesion molecules that prevent adhesion. Understanding the molecular mechanisms through which Dscams function is important for basic developmental neurobiology and has implications for human neurodevelopmental defects. We are approaching this problem through a variety of genetic and molecular methods, including domain-specific mutations in the Dscam and Dscaml1 genes, and biochemistry examining protein/protein interactions.